The rate at which pharmaceutically active compounds dissolve in gastrointestinal fluids is of crucial importance in the design and use of orally administered medications. The active compound must be dissolved before it can be absorbed by the body. The rate at which the active substance enters into solution is known in the art as the dissolution rate, and the determination of the dissolution rate in vitro is known as dissolution testing.
Dissolution testing provides a better understanding of the amount of a pharmaceutically active compound that is available at a particular absorption site at various times. In addition, establishing a relationship between dosage form and availability of one or more pharmaceutically active compounds at certain absorption sites, as well as the systemic blood levels of such active compounds, facilitates the development of specialized delivery techniques.
The concept of using in vitro data to predict or model in vivo behavior, referred to as in vitro-in vivo correlation, or IVIVC, is of great interest to practitioners in the pharmaceutical and medical industries, among others. Test methods with good IVIVC are much more capable of detecting problems with existing formulations and in the development of new formulations. Systems which correlate closely with the dissolution and absorption data obtained in vivo can be used in developing dosage forms as well as in the production, scale-up, determination of lot-to-lot variability, testing of new dosage strengths, testing of minor formulation changes, testing after changes in the site of manufacture and for determining bio-equivalence.
Various methods and devices for dissolution measurement are well known and described in the art.
The US Food and Drug Administration (US FDA) has issued guidelines on the relative value of different levels of correlation that are more or less desirable in in vitro testing (Guidance for Industry, Extended Release Oral Dosage Forms: Application of In vitro/In vivo Correlations, September 1997). A “Level A” correlation is one that predicts the entire in vivo time course from the in vitro data. A “Level B” correlation is one that uses statistical moment analysis. The mean dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A “Level C” correlation establishes a single point relationship between a dissolution parameter and a pharmacokinetic parameter.
Level B and Level C correlations do not reflect the complete shape of the plasma concentration-time curve, which is a graphical representation of the changes in concentration of one or more active substances over the time required for the active substances to pass through the patient's body. Thus, A Level A correlation is considered to be the most informative and is recommended by the USFDA wherever possible. Having a high level of correlation, e.g., a Level A correlation, can reduce the amount of in vivo testing necessary for new formulations and can, therefore, be very valuable to practitioners.
In many previously developed flow-through dissolution testing systems, only one cell was used per test. There are multiple cell systems available commercially, but the cells in these systems are arranged in parallel so that each cell is independent of the other and, hence, they function as a plurality of single cell systems. Furthermore, such systems used cells which were in open communication with the environment. In other words, the one or more cells used in earlier dissolution testing systems had no lids or covers and, therefore, fluids could be freely exchanged between the chambers and the ambient environment, whether or not intended by the users.
The United States Pharmcopeia (USP) is a non-governmental, official public standards-setting authority for prescription and over-the-counter medicines and other healthcare products manufactured or sold in the United States. USP also sets widely recognized standards for food ingredients and dietary supplements, including standards for the quality, purity, strength, and consistency of such products. The USP (USP24, pages 1941-1951) describes seven different sets of apparatus for performing dissolution testing. Apparatus 1 and 2 in section <711> (pages 1941-1942) are essentially containers with a suitable stirring device into which is placed a fixed volume of dissolution medium, and the formulation being tested. Samples of the medium are withdrawn at various times and analyzed for dissolved active substance to determine the rate of dissolution. Section <724> (pages 1944-1951) describes various apparatus designed to test dissolution of extended release, delayed release, and transdermal delivery systems. Apparatus 3 (extended release) uses a reciprocating cylinder, Apparatus 4 (extended release) uses a flow-through cell, Apparatus 5 (transdermal) utilizes a paddle over a disk, Apparatus 6 (transdermal) uses a cylinder design, and Apparatus 7 (transdermal) uses a reciprocating holder. Apparatus 1, 2, 3, 5, 6, and 7 use a fixed volume of the dissolution medium. Apparatus 4 uses a continuous flow of dissolution medium. In all cases the volume of dissolution medium used is sufficient to completely dissolve the test substance, frequently known as sink conditions.
For many active substances and dosage forms the principles behind the USP dissolution tests are limiting. These limitations are true for those active substances for which the rate of dissolution is dependent upon the amount of said active substances already dissolved in the release medium. These include, but are not limited to complexes between active substances and ion exchange resins, and poorly soluble active substances. Some combinations of ion exchange resin and active substances form an equilibrium state under fixed volume conditions such that some of the drug remains on the resin, even at infinite time and under sink conditions. This will give rise to incomplete dissolution when using test methods similar to those described in USP24. When an active substance has been dissolved in the gastrointestinal system it is absorbed by the body through the walls of the gastrointestinal system. This results in a decrease in the concentration of the active substance in solution. In the case where the active substance is in equilibrium with the polymeric complex, as described above, this decrease in concentration will displace the equilibrium such that more active substance will be released. As absorption by the body continues, the release of drug from the polymeric complex will be essentially complete. It is therefore clear that the in vitro test as described above, indicating incomplete release, is not predictive of the actual release experienced in vivo. A similar deficiency will occur with poorly soluble materials when sink conditions do not occur in vivo. The concentration will reach saturation, and the dissolution rate will then depend on the rate of absorption of the active substance by the body. The fixed volume limitation does not apply to the flow-through equipment (Apparatus 4 as described in USP 24). In this case the test material is constantly exposed to fresh dissolution medium, where the concentration of active substance is always zero. While this eliminates the equilibrium constraint, and therefore does permit the complete dissolution of such active substances, it still does not accurately simulate the actual physiological condition wherein the concentration of active substance is zero only at the start. With formulations controlled by equilibrium or limited solubility, it is clear to one skilled in the art that the USP methods cannot be expected to give good IVIVC without further mathematical manipulation of the data.
In the current art, Level A IVIVC is generally obtained by the use of mathematical tools to convert the in vitro data into predicted plasma concentration curves, or similar pharmacokinetic data that reflect the entire time course of the drug in the body (i.e., the total time required for the active substance(s) to pass through the body). While this is currently acceptable to the regulatory authorities, it is not completely satisfactory. The value of a mathematical model is frequently related to the number of independent variables used to adjust the model to fit the in vivo data and, as a guideline the USFDA, recommends no more than three independent variables.
The conditions that affect rate of dissolution in the gastro-intestinal system are known to vary with position of the active substance(s) in the body's gastro-intestinal system. There have been attempts to simulate these local variations in in vitro testing. One main focus has been on the very large pH change between the stomach and upper GI. This change is large enough to have a very serious effect on the solubility of some active substances. For example, diclofenac sodium is essentially insoluble at the low pH of the stomach, but is soluble at the near neutral conditions of the upper GI. In the current art this change of pH has been addressed in two ways. The first has been to change the fluid used in the dissolution test, for example start with gastric fluid and then empty and refill the test apparatus with intestinal fluid. The second has been to change the pH of the fluid in the test apparatus gradually, while running the test, by addition of a higher pH solution. Neither of these methods adequately simulates the pH change in vivo because in both methods all of the formulation experiences the pH change at the same time, whereas in vivo the pH change is controlled by gastric emptying, which causes a gradual transfer of the disintegrated formulation so that different portions of the formulation experience the pH changes at different times. In U.S. Pat. No. 5,807,115, Hu states that it is difficult to move an already disintegrated solid sample. Hu uses this conclusion to justify the gradual change of pH described above. A method that has been used to solve the problem associated with the USP fixed volume and flow-through methods has been the continuous flow cell, or chamber, in which either the contents of the cell or chamber are stirred, or a part of the effluent is recycled to the cell or chamber. This allows equilibrium effects to be simulated and evaluated.
Previous techniques for correlating in vitro and in vivo dissolution data have, generally, been limited to accounting for such factors as interactions with salts, enzymes, the ionic strength and pH of the medium and temperature. Discrepancies between in vitro and in vivo values of dissolution and absorption have previously been corrected for by transformation of data using functions added to existing mathematical models, such as by applying intestinal weighting functions, which transformations may not allow for physiological interpretation.
With development of more advanced dosage forms, especially for formulations that provide a delayed release of active compound, better predictive models are necessary. Thus, there was a need for an integrated assessment of the in vitro dissolution of a pharmaceutical formulation and the absorption of an active compound from such formulation, which parameters had previously been considered separately. There was also a need for an in vitro dissolution test that takes into account the absorption of the active substance by the body and the presence of dissolved active substance during the dissolution. An in vitro dissolution test that is able to demonstrate Level A IVIVC without the need for mathematical models to transform the in vitro data was also needed. Finally, an in vitro test was needed that could be used with different dosage forms of the same active ingredient that would produce Level A IVIVC for other dosage forms without the need for different test conditions for each dosage form.
To address the aforesaid shortcomings, dissolution test apparatus having at least two cells arranged in series have been developed, as described in U.S. Pat. No. 6,799,123 and U.S. Patent Application Publication Nos. 2007/0092404 and 2007/0160497. The dissolution testing systems described in these patent documents are very similar to one another. All of them have at least a first continuous flow cell and a second continuous flow cell, arranged in series. Each cell has an interior chamber through which media are passed and the media simulate various bodily fluids, such as gastric and intestinal fluids. Each cell also has a tight-fitting lid which separates the chamber from the exterior, ambient environment, which is believed to permit more accurate simulation of the digestion and absorption processes which occur in the body in vivo. The media (simulated bodily fluids) are provided to the chamber of each cell from one or more reservoirs by using pumps. A sample addition port provided in each tight-fitting lid enables the users to pass a dosage form having one or more active substances into the chamber to contact the media. One or more of the cells may have a dip tube and Tee assembly which allows for passage of media and some undissolved solids from the chamber of a particular cell to the chamber of the next downstream cell, when desired. Each of the cells is typically equipped with a stirring device to facilitate dissolution of active substance into the media inside the chamber. Various other inlets, outlets and ports are also provided for passing media and other materials to the chamber, as well as for taking samples for analysis during continuous operation of the dissolution test system, i.e., without having to open the chambers. Heating and insulating devices are also provided for controlling the temperature of the media in the chambers. Various analytical devices are provided to test for presence of active ingredients, as well as to measure the temperature and pH of the media in each chamber.
Pharmaceutical dosage forms may introduced into the cells by various manual means including, but not limited to, removal of the cover, dropping the dosage form into the chamber and replacement of the cover. As mentioned above, the apparatus described in U.S. Pat. No. 6,799,123 allows a dosage form to be added through the sample addition port, which is sealingly filled with a stopper which is removed while the dosage form is dropped in, and then replaced. Both of these manual methods of providing dosage forms to the cells require temporarily stopping the pumps, exposing the chamber to the ambient environment while the dosage form is added, and then restarting the pumps after the chamber is re-sealed.
Active substances cannot provide pharmaceutical benefits until absorbed into the tissues and blood of the body, which first requires that they be dissolved. The in vivo dissolution and absorption of active substances in the human gastro-intestinal system are understood to proceed, generally, as follows. Dissolution of the active substance may or may not begin in the mouth, which is more technically referred to as the buccal region of the gastro-intestinal system. If at least a portion of the active substance dissolves in the buccal region, then at least a portion of the dissolved active substance is likely to be absorbed into the tissues and blood proximate to the buccal region. Once past the buccal region, the active substances are not exposed to the ambient environment, but rather only to the interior conditions of each portion of the gastro-intestinal system. In vivo, some of the dissolved active substances, as well as most of the remaining solid, undissolved active substances are passed to the stomach, or gastric region, for further dissolution and absorption by the tissues and blood vessels proximate to the gastric region. From there, some of the dissolved active substances, as well as any remaining solid, undissolved active substances, pass from the gastric region into the small and large intestines, or more generally, the intestinal region, where solid, undissolved active substances are further dissolved and, hopefully, most of the dissolved active substances still present in the intestinal fluids are absorbed into the blood stream, more technically referred to, generally, as the circulatory region. However, solid, undissolved particles, if any, remaining in the intestines are not taken up by the circulatory region, but rather, they are passed down the remainder of the intestinal tract and eliminated from the body as waste.
Based on the foregoing progression of active substances through the gastro-intestinal system, in vivo, the various cells and chambers used to simulate conditions in the buccal and gastric regions (in vitro) must be capable of passing undissolved solids, up to a certain size, along with the liquid media and dissolved active substances, to chambers which simulate the gastric and intestinal regions, respectively. However, the chamber or chambers which simulate the intestinal region must be capable of retaining solid, undissolved particles, while passing media and dissolved active substances to the chamber or chambers which simulate the circulatory region. These requirements for the intestinal chambers are accomplished using a filter in the chamber at the outlet which leads to the downstream circulatory chamber, as explained in U.S. Pat. No. 6,799,123.
In U.S. Patent Application Publication Nos. 2007/0092404 and 2007/0160497, improved continuous flow dissolution test apparati, similar to that described in U.S. Pat. No. 6,799,123 are disclosed, along with methods for using them. In particular, U.S. Patent Application Publication No. 2007/0092404 describes using a filter support in the chamber of the second cell, positioned between the filter and the base (interior bottom surface) of the chamber to prevent distortion of the filter as it collects undissolved solids thereon.
On the other hand, U.S. Patent Application Publication No. 2007/0160497 discloses a sample holder device which operates with the sample addition port of the lid of a cell to enable addition and removal of a dosage form to the chamber within the same cell, during continuous operation of the multiple flow-through cell dissolution test system, without having to stop the flow of media or expose the contents of the chamber to the ambient environment. More particularly, the sample holder includes a tower removeably affixed to the lid of the cell at the sample addition port. A plunger is slidable within an interior region of the tower, between a “raised” position and an “extended” position. A basket for retaining or holding a dosage form is attached to the distal end of the plunger and is moved into and out of the chamber with the aforesaid sliding movement of the plunger. The basket is made of wire or mesh to permit media in the chamber to flow through and contact the dosage form for dissolution of active substance from the dosage form.
In operation, as described in U.S. Patent Application Publication No. 2007/0160497, prior to beginning the flow of media into the cells, the dosage form is placed in the basket of a sample holder device, the plunger is slid into the “raised” position (i.e., the basket is held above and outside the chamber of the cell) and the tower of the sample holder is removably affixed to the lid. After media is provided to the chambers and the system has reached equilibrium (i.e., the flow rates from each pump, the media volumes and pH in each chamber are within the desired ranges), the plunger may moved to its “extended” position, placing the dosage form in contact with the media in the chamber, without having to stop the media flow or expose the chamber to the ambient environment. The basket and dosage form may even be raised back out of the media during continuous operation of the flow-through system. However, the sample holder may not be removed from the lid without shutting off the flow of media and exposing the chamber and its contents to the ambient environment and, therefore, a second dosage form cannot be added for testing, nor can the original dosage form be removed from the cell entirely for inspection or insertion into a different cell in the system. This arrangement, while an improvement upon previous dissolution technology, still presents some limitations in practice.